Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators

ABSTRACT

Compounds in accord with Formula I: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , L, A, B, D, E, m, n, x and y are as defined in the description, processes for the preparation of such compounds and to new intermediates employed in the preparation thereof, pharmaceutical compositions containing such compounds, and the use of such compounds in therapy and for the treatment of diseases mentioned in the specification.

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds which are potentiatorsof glutamate receptors, methods for their preparation, pharmaceuticalcompositions containing them and their use in therapy.

The metabotropic glutamate receptors (mGluR) constitute a family ofGTP-binding-protein (G-protein) coupled receptors that are activated byglutamate, and have important roles in synaptic activity in the centralnervous system, including neural plasticity, neural development andneurodegeneration.

Activation of mGluRs in intact mammalian neurons elicits one or more ofthe following responses: activation of phospholipase C; increases inphosphoinositide (PI) hydrolysis; intracellular calcium release;activation of phospholipase D; activation or inhibition of adenylcyclase; increases or decreases in the formation of cyclic adenosinemonophosphate (cAMP); activation of guanylyl cyclase; increases in theformation of cyclic guanosine monophosphate (cGMP); activation ofphospholipase A₂; increases in arachidonic acid release; and increasesor decreases in the activity of voltage- and ligand-gated ion channels(Schoepp et al., 1993, Trends Pharmacol. Sci., 14:13; Schoepp, 1994,Neurochem. Int., 24:439; Pin et al., 1995, Neuropharmacology 34:1; Bordi& Ugolini, 1999, Prog. Neurobiol. 59:55).

Eight mGluR subtypes have been identified, which are divided into threegroups based upon primary sequence similarity, signal transductionlinkages, and pharmacological profile. Group-I includes mGluR1 andmGluR5, which activate phospholipase C and the generation of anintracellular calcium signal. The Group-II (mGluR2 and mGluR3) andGroup-III (mGluR4, mGluR6, mGluR7, and mGluR8) mGluRs mediate aninhibition of adenylyl cyclase activity and cyclic AMP levels. For areview, see Pin et al., 1999, Eur. J. Pharmacol., 375:277-294.

Members of the mGluR family of receptors are implicated in a number ofnormal processes in the mammalian CNS, and are important targets forcompounds for the treatment of a variety of neurological and psychiatricdisorders. Activation of mGluRs is required for induction of hippocampallong-term potentiation and cerebellar long-term depression (Bashir etal., 1993, Nature, 363:347; Bortolotto et al., 1994, Nature, 368:740;Aiba et al., 1994, Cell, 79:365; Aiba et al., 1994, Cell, 79:377). Arole for mGluR activation in nociception and analgesia also has beendemonstrated (Meller et al., 1993, Neuroreport, 4: 879; Bordi & Ugolini,1999, Brain Res., 871:223). In addition, mGluR activation has beensuggested to play a modulatory role in a variety of other normalprocesses including synaptic transmission, neuronal development,apoptotic neuronal death, synaptic plasticity, spatial learning,olfactory memory, central control of cardiac activity, waking, motorcontrol and control of the vestibulo-ocular reflex (Nakanishi, 1994,Neuron, 13:1031; Pin et al., 1995, Neuropharmacology, supra; Knopfel etal., 1995, J. Med. Chem., 38:1417).

Recent advances in the elucidation of the neurophysiological roles ofmGluRs have established these receptors as promising drug targets in thetherapy of acute and chronic neurological and psychiatric disorders andchronic and acute pain disorders. Because of the physiological andpathophysiological significance of the mGluRs, there is a need for newdrugs and compounds that can modulate mGluR function.

SUMMARY OF THE INVENTION

This invention provides, as one object, compounds of Formula I,

wherein:

R¹ is selected from the group consisting of H, hydroxy, F, Cl, Br, I,nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl, O-alkenyl,alkynyl, O-alkynyl, methylenedioxy and ethylenedioxy;

L is selected from the group consisting of alkylene, alkenylene andalkynylene wherein any hydrogen atom of L may be independentlysubstituted with one or more substituents selected from the groupconsisting of hydroxy, F, Cl, Br, I, alkyl, alkylhalo and O-alkyl;

A is selected from the group consisting of aryl and heteroaryl;

B is selected from the group consisting of alkylene, aryl, heteroaryl,cycloalkyl and heterocycloalkyl;

D is selected from the group consisting of alkylene, O,O-alkylene andalkylene-O;

E is selected from the group consisting of aryl, heteroaryl, cycloalkyland heterocycloalkyl;

m and n are independently selected from the group consisting of 0, 1, 2,3 and 4;

x and y are independently selected from the group consisting of 0 and 1;

wherein any of A, B and E may be substituted with up to 4 substituentsindependently selected from the group consisting of hydroxy, F, Cl, Br,I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, alkyleneOR², O-alkyleneOR², (CO)R²,O(CO)R², alkyleneO(CO)R², alkylene(CO)R², O-alkylene(CO)R², CO₂R,alkyleneCO₂R², O-alkyleneCO₂R², alkylenecyano, O-alkylenecyano,O(CN)OR², NR²R³, alkyleneNR²R³, O-alkyleneNR²R³, (CO)NR²R³,alkylene(CO)NR²R³, O—(CO)NR²R³, O-alkylene(CO)NR²R³, NR²(CO)R³,alkyleneNR²(CO)R³, O-alkyleneNR²(CO)R³, NR²(CO)NR³R⁴,alkyleneNR²(CO)NR³R⁴, and

wherein R² and R⁴ are independently selected from the group consistingof H and alkyl, and R³ is selected from the group consisting of H, alkyland alkylene-NR²R⁴.

Another object of the invention is to provide a pharmaceuticalcomposition comprising a compound according to Formula I together with apharmaceutically acceptable carrier or excipient.

Yet another object of the invention is a method for the treatment orprevention of neurological and psychiatric disorders associated withglutamate dysfunction in an animal in need of such treatment. The methodcomprises the step of administering to the animal a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticalcomposition thereof. Preferably, the animal is a mammal; more preferablya human being.

Still another object of the invention is the use of a compound accordingto Formula I, or a pharmaceutically acceptable salt or solvate thereof,for the manufacture of a medicament for the treatment of any of theconditions discussed herein.

Another object of the invention provides a compound of Formula I, or apharmaceutically acceptable salt or solvate thereof, for use in therapy.

The invention additionally provides processes for the preparation ofcompounds of Formula I. General and specific processes are discussed inmore detail below.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present invention is based upon the discovery of compoundscontemplated to be useful as pharmaceuticals, in particular asmodulators of metabotropic glutamate receptors. More particularly,compounds of the present invention exhibit activity as potentiators ofthe mGluR2 receptor, and are contemplated to be useful in therapy, inparticular for the treatment of neurological and psychiatric disordersassociated with glutamate dysfunction.

DEFINITIONS

Unless specified otherwise within this specification, the nomenclatureused in this specification generally follows the examples and rulesstated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F,and H, Pergamon Press, Oxford, 1979, which is incorporated by referencesherein for its exemplary chemical structure names and rules on namingchemical structures. Optionally, a name of a compound may be generatedusing a chemical naming program: ACD/ChemSketch, Version 5.09/September2001, Advanced Chemistry Development, Inc., Toronto, Canada.

The term “alkyl” as used herein means a straight- or branched-chainhydrocarbon radical having from one to six carbon atoms, and includesmethyl, ethyl, propyl, isopropyl, t-butyl and the like.

The term “alkenyl” as used herein means a straight- or branched-chainalkenyl radical having from two to six carbon atoms, and includesethenyl, 1-propenyl, 1-butenyl and the like.

The term “alkynyl” as used herein means a straight- or branched-chainalkynyl radical having from two to six carbon atoms, and includes1-propynyl (propargyl), 1-butynyl and the like.

The term “cycloalkyl” as used herein means a cyclic group (which may beunsaturated) having from three to seven carbon atoms, and includescyclopropyl, cyclohexyl, cyclohexenyl and the like.

The term “heterocycloalkyl” as used herein means a three- toseven-membered cyclic group (which may be unsaturated) having at leastone heteroatom selected from the group consisting of N, S and O, andincludes piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl andthe like.

The term “alkoxy” as used herein means a straight- or branched-chainalkoxy radical having from one to six carbon atoms and includes methoxy,ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.

The term “halo” as used herein means halogen and includes fluoro,chloro, bromo, iodo and the like, in both radioactive andnon-radioactive forms.

The term “alkylene” as used herein means a difunctional branched orunbranched saturated hydrocarbon radical having one to six carbon atoms,and includes methylene, ethylene, n-propylene, n-butylene and the like.

The term “alkenylene” as used herein means a difunctional branched orunbranched hydrocarbon radical having two to six carbon atoms and havingat least one double bond, and includes ethenylene, n-propenylene,n-butenylene and the like.

The term “alkynylene” as used herein means a difunctional branched orunbranched hydrocarbon radical having two to six carbon atoms and havingat least one triple bond, and includes ethynylene, n-propynylene,n-butynylene and the like.

The term “aryl” as used herein means an aromatic group having five totwelve atoms, and includes phenyl, naphthyl and the like.

The term “heteroaryl” means an aromatic group which includes at leastone heteroatom selected from the group consisting of N, S and O, andincludes groups and includes pyridyl, indolyl, furyl, benzofuryl,thienyl, benzothienyl, quinolyl, oxazolyl and the like.

The term “pharmaceutically acceptable salt” means either an acidicaddition salt or a basic addition salt which is compatible with thetreatment of patients.

A “pharmaceutically acceptable acidic addition salt” is any non-toxicorganic or inorganic acidic addition salt of the base compoundsrepresented by Formula I or any of its intermediates. Illustrativeinorganic acids which form suitable salts include hydrochloric,hydrobromic, sulfuric and phosphoric acid and acid metal salts such assodium monohydrogen orthophosphate and potassium hydrogen sulfate.Illustrative organic acids which form suitable salts include the mono-,di- and tricarboxylic acids. Illustrative of such acids are, forexample, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric,fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic,benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic,2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids suchas methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either themono- or di-acid salts can be formed, and such salts can exist in eithera hydrated, solvated or substantially anhydrous form. In general, theacidic addition salts of these compounds are more soluble in water andvarious hydrophilic organic solvents, and generally demonstrate highermelting points in comparison to their free base forms. The selectioncriteria for the appropriate salt will be known to one skilled in theart. Other non-pharmaceutically acceptable salts e.g. oxalates may beused for example in the isolation of compounds of Formula I forlaboratory use, or for subsequent conversion to a pharmaceuticallyacceptable acidic addition salt.

A “pharmaceutically acceptable basic addition salt” is any non-toxicorganic or inorganic base addition salt of the acid compoundsrepresented by Formula I or any of its intermediates. Illustrativeinorganic bases which form suitable salts include lithium, sodium,potassium, calcium, magnesium or barium hydroxides. Illustrative organicbases which form suitable salts include aliphatic, alicyclic or aromaticorganic amines such as methylamine, trimethyl amine and picoline orammonia. The selection of the appropriate salt may be important so thatan ester functionality, if any, elsewhere in the molecule is nothydrolyzed. The selection criteria for the appropriate salt will beknown to one skilled in the art.

The term “solvate” means a compound of Formula I or the pharmaceuticallyacceptable salt of a compound of Formula I wherein molecules of asuitable solvent are incorporated into a crystal lattice. A suitablesolvent is physiologically tolerable at the dosage administered as thesolvate. Examples of suitable solvents are ethanol, water and the like.When water is the solvent, the molecule is referred to as a hydrate.

The term “treat” or “treating” means to alleviate symptoms, eliminatethe causation of the symptoms either on a temporary or permanent basis,or to prevent or slow the appearance of symptoms of the named disorderor condition.

The term “therapeutically effective amount” means an amount of thecompound which is effective in treating the named disorder or condition.

The term “pharmaceutically acceptable carrier” means a non-toxicsolvent, dispersant, excipient, adjuvant or other material which ismixed with the active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

Compounds

Compounds of the invention conform generally to Formula I:

wherein:

R¹ is selected from the group consisting of H, hydroxy, F, Cl, Br, I,nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl, O-alkenyl,alkynyl, O-alkynyl, methylenedioxy and ethylenedioxy;

L is selected from the group consisting of alkylene, alkenylene andalkynylene wherein any hydrogen atom of L may be independentlysubstituted with one or more substituents selected from the groupconsisting of hydroxy, F, Cl, Br, I, alkyl, alkylhalo and O-alkyl;

A is selected from the group consisting of aryl and heteroaryl;

B is selected from the group consisting of alkylene, aryl, heteroaryl,cycloalkyl and heterocycloalkyl;

D is selected from the group consisting of alkylene, O,O-alkylene andalkylene-O;

E is selected from the group consisting of aryl, heteroaryl, cycloalkyland heterocycloalkyl;

m and n are independently selected from the group consisting of 0, 1, 2,3 and 4;

x and y are independently selected from the group consisting of 0 and 1;

wherein any of A, B and E may be substituted with up to 4 substituentsindependently selected from the group consisting of hydroxy, F, Cl, Br,I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, alkyleneOR², O-alkyleneOR², (CO)R²,O(CO)R², alkyleneO(CO)R², alkylene(CO)R², O-alkylene(CO)R², CO₂R,alkyleneCO₂R², O-alkyleneCO₂R², alkylenecyano, O-alkylenecyano,O(CN)OR², NR²R³, alkyleneNR²R³, O-alkyleneNR²R³, (CO)NR²R³,alkylene(CO)NR²R³, O—(CO)NR²R³, O-alkylene(CO)NR²R³, NR²(CO)R³,alkyleneNR²(CO)R³, O-alkyleneNR²(CO)R³, NR²(CO)NR³R⁴,alkyleneNR²(CO)NR³R⁴, and

wherein R² and R⁴ are independently selected from the group consistingof H and alkyl, and

R³ is selected from the group consisting of H, alkyl and alkylene-NR²R⁴.

In a particular embodiment, compounds are those in accord with Formula Iwherein m is 1, of Formula Ia:

wherein R¹, n, L, A, B, D, E, x and y are as defined for Formula I.

In another particular embodiment, compounds are those in accord withFormula I wherein m is 1, and x and y are each 0, of Formula Ib:

wherein R¹, n, L, A and B are as defined for Formula I.

In yet another particular embodiment, compounds are those in accord withFormula I wherein m is 1, x and y are each 0, A and B are both arylwherein aryl is phenyl, of Formula Ic:

wherein R¹, n and L are as defined for Formula I,wherein each phenyl may be substituted with up to 4 substituentsindependently selected from the group consisting of hydroxy, F, Cl, Br,I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, alkyleneOR², O-alkyleneOR², (CO)R²,O(CO)R², alkyleneO(CO)R², alkylene(CO)R², O-alkylene(CO)R², CO₂R,alkyleneCO₂R², O-alkyleneCO₂R², alkylenecyano, O-alkylenecyano,O(CN)OR², NR²R³, alkyleneNR²R³, O-alkyleneNR²R³, (CO)NR²R³,alkylene(CO)NR²R³, O—(CO)NR²R³, O-alkylene(CO)NR²R³, NR²(CO)R³,alkyleneNR²(CO)R³, O-alkyleneNR²(CO)R³, NR²(CO)NR³R⁴,alkyleneNR²(CO)NR³R⁴, andwherein R² and R⁴ are independently selected from the group consistingof H and alkyl, and

R³ is selected from the group consisting of H, alkyl and alkylene-NR²R⁴.

In compounds of a further embodiment of the invention L is an alkylenegroup.

In compounds of a further embodiment of the invention A is an arylgroup.

In compounds of a another embodiment A is a heteroaryl group.

In compounds of a another embodiment of the invention B is an arylgroup.

In compounds of a another embodiment of the invention D is an alkylenegroup.

In compounds of a another embodiment of the invention E is aheterocycloalkyl group.

It will be understood by those of skill in the art that when compoundsof the present invention have one or more chiral centers, the compoundsof the invention may exist in, and be isolated as, enantiomeric ordiastereomeric forms, or as a racemic mixture. The present inventionincludes any possible enantiomers, diastereomers, racemates or mixturesthereof, of a compound of Formula I. The optically active forms of thecompound of the invention may be prepared, for example, by chiralchromatographic separation of a racemate, by synthesis from opticallyactive starting materials or by asymmetric synthesis based on theprocedures described thereafter.

It will also be appreciated by those of skill in the art that certaincompounds of the present invention may exist as geometrical isomers, forexample E and Z isomers of alkenes. The present invention includes anygeometrical isomer of a compound of Formula I. It will further beunderstood that the present invention encompasses tautomers of thecompounds of Formula I.

It will also be understood by those of skill in the art that certaincompounds of the present invention may exist in solvated, for examplehydrated, as well as unsolvated forms. It will further be understoodthat the present invention encompasses all such solvated forms of thecompounds of Formula I.

Within the scope of the invention are also salts of the compounds ofFormula I. Generally, pharmaceutically acceptable salts of compounds ofthe present invention are obtained using standard procedures well knownin the art, for example, by reacting a sufficiently basic compound, forexample an alkyl amine with a suitable acid, for example, HCl or aceticacid, to afford a physiologically acceptable anion. It is also possibleto make a corresponding alkali metal (such as sodium, potassium, orlithium) or an alkaline earth metal (such as a calcium) salt by treatinga compound of the present invention having a suitably acidic proton,such as a carboxylic acid or a phenol with one equivalent of an alkalimetal or alkaline earth metal hydroxide or alkoxide (such as theethoxide or methoxide), or a suitably basic organic amine (such ascholine or meglumine) in an aqueous medium, followed by conventionalpurification techniques.

In one embodiment of the present invention, the compound of Formula Imay be converted to a pharmaceutically acceptable salt or solvatethereof, particularly, an acidic addition salt such as a hydrochloride,hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate,methanesulphonate or p-toluenesulphonate.

Specific examples of the present invention include the compounds I to18.1, illustrated in the following table, their pharmaceuticallyacceptable salts, hydrates, solvates, optical isomers, and combinationsthereof:

Example No. Structure Name 1.1

3-(2′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.2

3-(2′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.3

3-(2′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.4

3-[2′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.5

3-(2′-Piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.6

3-(4′-Phenoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.7

3-(4-Pyridin-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.8

3-[4′-(4-Methyl-piperazin-1-yl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.9

3-(4′-Fluoro-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.10

3-(4′-Phenoxy-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.11

3-(3-Pyridin-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.12

3-(4′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.13

3-(4-Pyridin-4-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.14

3-(4-Pyrimidin-5-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.15

3-(4-Thiophen-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.16

3-(4-Thiophen-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.17

3-(3-Thiophen-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.18

3-(3-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.19

3-(3′-Diethylaminomethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.20

3-(3′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.21

3-[3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-3-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.22

3-(4′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.23

3-(4′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.24

3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.25

3-(4′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.26

3-(3′-Morpholin-4-ylmethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.27

3-(4′-Diethylaminomethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.28

3-(4′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.28

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-3-carboxylicacid (2-dimethyl amino-ethyl)-amide 1.30

3-{4-[6-(2-Morpholin-4-yl-ethylamino)-pyridin-3-yl]-benzyl}-1-oxa-3-aza-spiro[4.5]decan-2-one1.31

3-(4-Cyclohex-1-enyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.32

3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-3-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.33

3-(4′-Morpholin-4-ylmethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.34

3-(3′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.35

3-(3′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.36

3-[3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one 1.37

3-(3′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.38

3-(2′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.39

3-(3′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.40

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-yl methyl)-biphenyl-3-carbonitrile1.41

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbonitrile1.42

3-(3′-Methoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.43

3-(4′-Methoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.44

3-(2′,4′-Difluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.45

3-(3′,5′-Difluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.46

3-(3′,4′-Dimethoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.47

3-(2′-Methoxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.48

3-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.49

3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-one1.50

3-(4′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.51

3-[4′-(3-Hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.52

3-[4′-(Pyrrolidin-3-yloxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.53

3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one1.54

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbaldehyde1.55

3-(3-Pyridin-4-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 1.56

3-[5-(4-Fluoro-phenyl)-pyridin-2-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one1.57

3-(5-Cyclohex-1-enyl-pyridin-2-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one3.2

3-Biphenyl-4-ylmethyl-1-oxa-3-aza-spiro[4.5]decan-2-one 3.3

3-(4-Phenoxy-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 3.6

3-(5-Furan-2-yl-isoxazol-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one3.7

3-[3-(3-Fluoro-phenyl)-[1.2.4]oxadiazol-5-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one4.1

3-(3-Pyridin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 4.2

3-(3-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 4.3

3-(4-Pyridin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 4.4

3-(4-Pyrazin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 4.5

3-(4-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 5.1

3-(4-Cyclohexyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one 7.1

3-[4-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one7.2

3-[4′-(1-Methyl-pyrrolidin-3-yloxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one8.1

3-(4′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decane-2,8-dione9.1

[4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-ylmethoxy]-acetaldehyde 10.1

3-[4′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one11.1

3-[4′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one11.2

3-[3′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one11.3

3-[3′-(2-Methylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one12.1

3-[3′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one12.2

3-(3′-Hydroxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one13.1

3-[4′-(3-Hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one18.1

3-[3(4-morpholin-4-ylmethyl-phenyl)-prop-2-ynyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

Pharmaceutical Compositions

The compounds of the present invention may be formulated intoconventional pharmaceutical composition comprising a compound of FormulaI, or a pharmaceutically acceptable salt or solvate thereof, inassociation with a pharmaceutically acceptable carrier or excipient. Thepharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include, but are not limited to, powders,tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or table disintegrating agents. A solid carrier can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided compound of the invention, or the activecomponent. In tablets, the active component is mixed with the carrierhaving the necessary binding properties in suitable proportions andcompacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmoulds and allowed to cool and solidify.

Suitable carriers include, but are not limited to, magnesium carbonate,magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch,tragacanth, methyl cellulose, sodium carboxymethyl cellulose,low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which is thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions.For example, sterile water or water propylene glycol solutions of theactive compounds may be liquid preparations suitable for parenteraladministration. Liquid compositions can also be formulated in solutionin aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art. Exemplary compositions intended for oral use maycontain one or more coloring, sweetening, flavoring and/or preservativeagents.

Depending on the mode of administration, the pharmaceutical compositionwill include from about 0.05% w (percent by weight) to about 99% w, moreparticularly, from about 0.10% w to 50% w, of the compound of theinvention, all percentages by weight being based on the total weight ofthe composition.

A therapeutically effective amount for the practice of the presentinvention can be determined by one of ordinary skill in the art usingknown criteria including the age, weight and response of the individualpatient, and interpreted within the context of the disease which isbeing treated or which is being prevented.

Medical Use

It is contemplated that compounds of the present invention will exhibitactivity as pharmaceuticals, in particular as modulators of metabotropicglutamate receptors. More particularly, the compounds of the presentinvention exhibit activity as potentiators of the mGluR2 receptor, andare contemplated to be useful in therapy, in particular for thetreatment of neurological and psychiatric disorders associated withglutamate dysfunction in an animal.

More specifically, the neurological and psychiatric disorders include,but are not limited to, disorders such as cerebral deficit subsequent tocardiac bypass surgery and grafting, stroke, cerebral ischemia, spinalcord trauma, head trauma, perinatal hypoxia, cardiac arrest,hypoglycemic neuronal damage, dementia (including AIDS-induceddementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateralsclerosis, ocular damage, retinopathy, cognitive disorders, idiopathicand drug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, cerebral deficits secondary to prolonged statusepilepticus, migraine (including migraine headache), urinaryincontinence, substance tolerance, substance withdrawal (including,substances such as opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis,schizophrenia, anxiety (including generalized anxiety disorder, panicdisorder, social phobia, obsessive compulsive disorder, andpost-traumatic stress disorder (PTSD)), mood disorders (includingdepression, mania, bipolar disorders), circadian rhythm disorders(including jet lag and shift work), trigeminal neuralgia, hearing loss,tinnitus, macular degeneration of the eye, emesis, brain edema, pain(including acute and chronic pain states, severe pain, intractable pain,neuropathic pain, inflammatory pain, and post-traumatic pain), tardivedyskinesia, sleep disorders (including narcolepsy), attentiondeficit/hyperactivity disorder, and conduct disorder.

The invention thus provides a use of any of the compounds according toFormula I, or a pharmaceutically acceptable salt or solvate thereof, forthe manufacture of a medicament for the treatment of any of theconditions discussed above.

Additionally, the invention provides a method for the treatment of asubject suffering from any of the conditions discussed above, whereby aneffective amount of a compound according to Formula I or apharmaceutically acceptable salt or solvate thereof, is administered toa patient in need of such treatment. The invention also provides acompound of Formula I or pharmaceutically acceptable salt or solvatethereof, as hereinbefore defined for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The term “therapeutic” and “therapeutically” should beconstrued accordingly. The term “therapy” within the context of thepresent invention further encompasses the administration of an effectiveamount of a compound of the present invention, to mitigate either apre-existing disease state, acute or chronic, or to mitigate a recurringcondition. This definition also encompasses prophylactic therapies forprevention of recurring conditions and continued therapy for chronicdisorders. In use for therapy in a warm-blooded animal such as a human,the compounds of the present invention may be administered in the formof a conventional pharmaceutical composition by any route includingorally, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracically, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints. In preferred embodiments of the invention, the route ofadministration is oral, intravenous, or intramuscular.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, who determines the individualregimen and dosage level for a particular patient.

As mentioned above, the compounds described herein may be provided ordelivered in a form suitable for oral use, for example, in a tablet,lozenge, hard and soft capsule, aqueous solution, oily solution,emulsion, and suspension. Alternatively, the compounds may be formulatedinto a topical administration, for example, as a cream, ointment, gel,spray, or aqueous solution, oily solution, emulsion or suspension. Thecompounds described herein also may be provided in a form that issuitable for nasal administration, for example, as a nasal spray, nasaldrops, or dry powder. The compounds can be administered to the vagina orrectum in the form of a suppository. The compounds described herein alsomay be administered parentally, for example, by intravenous,intravesicular, subcutaneous, or intramuscular injection or infusion.The compounds can be administered by insufflation (for example as afinely divided powder). The compounds may also be administeredtransdermally or sublingually.

In addition to their use in therapeutic medicine, the compounds ofFormula I, or salts thereof, are useful as pharmacological tools in thedevelopment and standardization of in vitro and in vivo test systems forthe evaluation of the effects of inhibitors of mGluR-related activity inlaboratory animals as part of the search for new therapeutics agents.Such animals include, for example, cats, dogs, rabbits, monkeys, ratsand mice.

Process for Preparing Compounds

Compounds of the present invention can be prepared by various syntheticprocesses. The selection of a particular process to prepare a givencompound is within the purview of the person of skill in the art. Thechoice of particular structural features and/or substituents maytherefore influence the selection of one process over another.

Within these general guidelines, the following processes can be used toprepare exemplary subsets of compounds of this invention. Unlessindicated otherwise, the variables described in the following schemesand processes have the same definitions as those given for Formula Iabove.

In one process, for example, compounds of Formula I wherein L is analkylene moiety and A and B are phenyl groups may be prepared as shownin Scheme 1, below:

Alternatively, as shown in Scheme 2, below, such compounds may beprepared by coupling iodo intermediate (v) with aryl tin reagent (vi):

Many variations of the foregoing processes and additions thereto appearthroughout the examples that follow. The person of ordinary skill in theart thus will appreciate that the compounds of this invention can beprepared by following or adapting one or more of the processes disclosedherein.

The invention is further illustrated by way of the following examples,which are intended to elaborate several embodiments of the invention.These examples are not intended to, nor are they to be construed to,limit the scope of the invention. It will be clear that the inventionmay be practiced otherwise than as particularly described herein.Numerous modifications and variations of the present invention arepossible in view of the teachings herein and, therefore, are within thescope of the invention.

General Methods

The following abbreviations are used in the examples:

BOC tert-butoxycarbonyl BSA Bovine Serum Albumin CCD Charge CoupledDevice CRC Concentration Response Curve DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DHPG3,5-dihydroxyphenylglycine; DIBAL diisobutylaluminum hydride DMFN,N-dimethylformamide DMSO dimethyl sulfoxide EDTA Ethylene DiamineTetraacetic Acid Et₃N triethylamine EtOAc Ethyl acetate FLIPRFluorometric Imaging Plate reader GC/MS gas chromatograph coupled massspectroscopy GHEK Human Embryonic Kidney expressing GlutamateTransporter HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid(buffer) IP₃ inositol triphosphate MCPBA 3-chloroperbenzoic acid MeOHmethanol NMP N-Methylpyrrolidinone NMR nuclear magnetic resonance PCCpyridinium chlorochromate

ppm parts per million

RT room temperature SPE solid phase extraction TFA trifluoroacetic acidTHF tetrahydrofuran TLC thin layer chromatography

All starting materials are commercially available or earlier describedin the literature. The ¹H and ¹³C NMR spectra were recorded either onBruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300,400 and 400 MHz for ¹H NMR respectively, using TMS or the residualsolvent signal as reference, in deuterated chloroform as solvent unlessotherwise indicated. All reported chemical shifts are in ppm on thedelta-scale, and the fine splitting of the signals as appearing in therecordings (s: singlet, br s: broad singlet, d: doublet, t: triplet, q:quartet, m: multiplet).

Analytical in line liquid chromatography separations followed by massspectra detections, were recorded on a Waters LCMS consisting of anAlliance 2795 (LC) and a ZQ single quadrupole mass spectrometer. Themass spectrometer was equipped with an electrospray ion source operatedin a positive and/or negative ion mode. The ion spray voltage was ±3 kVand the mass spectrometer was scanned from m/z 100-700 at a scan time of0.8 s. To the column, X-Terra MS, Waters, C8, 2.1×50 mm, 3.5 mm, wasapplied a linear gradient from 5% to 100% acetonitrile in 10 mM ammoniumacetate (aq.), or in 0.1% TFA (aq.).

Preparative reversed phase chromatography was run on a Gilsonpreparative HPLC with UV detection at 254 nm, using a Chiralpak AD0.46×25 cm column (Daicel Chemical Industries, Ltd.).

Purification of products were also done using Chem Elut ExtractionColumns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPEColumns (Varian, cat #12256018; 12256026; 12256034), or by flashchromatography in silica-filled glass columns.

The pharmacological properties of the compounds of the invention can beanalyzed using standard assays for functional activity. Examples ofglutamate receptor assays are well known in the art as described in, forexample, Aramori et al., 1992, Neuron, 8:757; Tanabe et al., 1992,Neuron, 8:169; Miller et al., 1995, J. Neuroscience, 15:6103; Balazs, etal, 1997, J. Neurochemistry, 1997, 69:151. The methodology described inthese publications is incorporated herein by reference. Conveniently,the compounds of the invention can be studied by means of an assay thatmeasures the mobilization of intracellular calcium, [Ca²⁺]_(i) in cellsexpressing mGluR2.

A [³⁵S]-GTPγS binding assay was used to functionally assay mGluR2receptor activation. The allosteric activator activity of compounds atthe human mGluR2 receptor were measured using a [³⁵S]-GTPγS bindingassay with membranes prepared from CHO cells which stably express thehuman mGluR2. The assay is based upon the principle that agonists bindto G-protein coupled receptors to stimulate GDP-GTP exchange at theG-protein. Since [³⁵S]-GTPγS is a non-hydrolyzable GTP analog, it can beused to provide an index of GDP-GTP exchange and, thus, receptoractivation. The GTPγS binding assay therefore provides a quantitativemeasure of receptor activation.

Membranes were prepared from CHO cells stably transfected with humanmGluR2. Membranes (30 μg protein) were incubated with test compound (3nM to 300 μM) for 15 minutes at room temperature prior to the additionof 1 μM glutamate, and incubated for 30 min at 30° C. in 500 μL assaybuffer (20 mM HEPES, 100 mM NaCl, 1 mM MgCl₂), containing 30 μM GDP and0.1 nM [³⁵S]-GTPγS (1250 Ci/mmol). Reactions were carried out intriplicate in 2 mL polypropylene 96-well plates. Reactions wereterminated by vacuum filtration using a Packard 96-well harvester andUnifilter-96, GF/B filter microplates. The filter plates were washed4×1.5 mL with ice-cold wash buffer (10 mM sodium phosphate buffer, pH7.4). The filter plates were dried and 35 μL of scintillation fluid(Microscint 20) was added to each well. The amount of radioactivitybound was determined by counting plates on a Packard TopCount. Data wasanalyzed using GraphPad Prism, and EC₅₀ and E_(max) values (relative tothe maximum glutamate effect) were calculated using non-linearregression.

Generally, compounds of the present invention were active in the assaysdescribed herein at concentrations (or with EC₅₀ values) of less thanabout 10 μM. Preferred compounds of the invention have EC₅₀ values ofless than 1 μM; more preferred compounds of less than about 100 nM. Forexample, compounds of Examples 1.1, 1.6, 1.30, 1.49 and 3.2 have EC₅₀values of 326, 14, 1000, 381 and 95 nM, respectively.

EXAMPLES Example 1.13-(2′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one

3-(4-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (55 mg, 0.148 mmol)and benzylmopholine-2-boronic acid (49 mg, 0.222 mmol) were mixed inethylene glycol dimethyl ether (1 mL) and sodium carbonate (2M) aqueoussolution (1 mL). Tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄) (17mg, 0.0148 mmol) was added and the reaction mixture was heated at100˜110° C. for 1˜1.5 hours. The reaction was diluted withdichloromethane (DCM), washed with water (4 mL) and brine (4 mL). Theorganic phase was separated, dried over anhydrous sodium sulfate andconcentrated. The crude residue was purified on silica gel eluting with5-30% ethyl acetate in hexane to give the product as off-white solid (52mg, 83%). ¹H NMR (300 MHz, CDCl₃): δ 7.49 (m, 1H), 7.42 (d, 2H), 7.32(m, 5H), 4.5 (s, 2H), 3.65 (t, 4H), 3.39 (s, 2H), 3.18 (s, 2H), 2.36 (t,4H), 1.82 (m, 4H), 1.54 (m, 6H).

In a similar manner the following compounds were synthesized:

Example Structure Name Yield 1.2

3-(2′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneColorless oil,31 mg, 63% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.61 (d,1H), 7.34 (m, 7H), 4.5 (s, 2H), 3.47 (s, 2H), 3.17 (s, 2H), 2.41 (q,4H), 1.79 (m, 4H), 1.47 (m, 6H), 0.89 (t, 6H) 1.3

3-(2′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneColorless oil,32 mg, 61% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.59 (d,1H), 7.32 (m, 7H), 4.49 (s, 2H), 3.43 (s, 2H), 3.18 (s, 2H), 2.37 (m,4H), 2.19 (s, 6H), 2.14 (s, 3H), 1.8 (m, 4H), 1.57 (m, 6H) 1.4

3-[2′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 36 mg,69% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.48(m, 1H), 7.42 (d, 2H), 7.32 (m, 5H), 4.49 (s, 2H), 3.41 (s, 2H), 3.17(s, 2H), 2.38 (m, 8H), 2.26 (s, 3H), 1.83 (m, 4H), 1.49 (m, 6H) 1.5

3-(2′-Piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 81% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.52 (m, 1H),7.41 (d, 2H), 7.27 (m, 5H), 4.49 (s, 2H), 3.36 (s, 2H), 3.17 (s, 2H),2.81 (t, 4H), 2.31 (br, 4H), 1.82 (m, 5H), 1.47 (m,6H) 1.6

3-(4′-Phenoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite powder,74% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.57 (dd, 4H),7.36 (m, 4H), 7.08 (m, 5H), 4.49 (s, 2H), 3.15 (s, 2H), 1.79 (m, 4H),1.46 (m, 6H) 1.7

3-(4-Pyridin-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Whitesolid,quantitativeyield NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.01 (d,1H), 7.49 (m, 7H), 4.49 (s, 2H), 3.15 (s, 2H), 1.79 (m, 4H), 1.46 (m,6H) 1.8

3-[4′-(4-Methyl-piperazin-1-yl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite powder,quantitativeyield NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) =7.55 (m, 4H), 7.3 (dd, 2H), 7.01 (dd, 2H), 4.45 (s, 2H), 3.3 (t, 4H),3.13 (s, 2H), 2.65 (t, 4H), 2.39 (s, 3H), 1.78 (m, 4H), 1.47 (m, 6H) 1.9

3-(4′-Fluoro-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneYellow solid,45.9 mg, 91% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.55(m, 2H), 7.49 (m, 1H), 7.45 (m, 2H), 7.28 (m, 1H), 7.15 (t, 2H), 4.50(s, 2H), 3.15 (s, 2H), 1.80 (m, 4H), 1.47 (m, 6H) 1.10

3-(4′-Phenoxy-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown oil,40.5 mg, 66% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.56 (m,3H), 7.38 (m, 5H), 7.08 (m, 5H), 4.51 (s, 2H), 3.15 (s, 2H), 1.74 (m,4H), 1.50 (m, 6H) 1.11

3-(3-Pyridin-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Yellowoil24.5 mg,51% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.85 (m, 1H), 8.62(m, 1H), 7.88 (m, 1H), 7.44 (m, 6H), 4.52 (s, 2H), 3.16 (s, 2H), 1.80(m, 4H), 1.48 (m, 6H) 1.12

3-(4′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,38 mg, 93% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.55 (m,4H), 7.34 (d, 2H), 7.14 (t, 2H), 4.48 (s, 2H), 3.15 (s, 2H), 1.79 (m,4H), 1.45 (m, 6H) 1.13

3-(4-Pyridin-4-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Whitesolid,26 mg, 66% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.68 (d, 2H),7.66 (d, 2H), 7.51 (m, 2H), 7.39 (d, 2H), 4.49 (s, 2H), 3.15 (s, 2H),1.79 (m, 4H), 1.44 (m, 6H) 1.14

3-(4-Pyrimidin-5-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Colorlessoil,15 mg, 38% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 9.24 (br, 1H),8.98 (br, 2H), 7.6 (d, 2H), 7.45 (d, 2H), 4.51 (s, 2H), 3.16 (s, 2H),1.77 (m, 4H), 1.47 (m, 6H) 1.15

3-(4-Thiophen-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Whitesolid,34 mg, 86% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.62 (d, 2H),7.58 (d, 1H), 7.4 (d, 2H), 7.3 (t, 2H), 4.45 (s, 2H), 3.13 (s, 2H), 1.79(m, 4H), 1.44 (m, 6H) 1.16

3-(4-Thiophen-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Whitesolid,23 mg, 58% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.7 (d, 2H), 7.6(dd, 1H), 7.36 (m, 2H), 7.03 (d, 2H), 4.37 (s, 2H), 3.09 (s, 2H), 1.82(m, 4H), 1.45 (m, 6H) 1.17

3-(3-Thiophen-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Lightbrownoil, 45 mg,93% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.51 (m, 1H),7.43 (m, 2H), 7.41 (m, 3H), 7.20 (m, 1H), 4.48 (s, 2H), 3.14 (s, 2H),1.79 (m, 4H), 1.45 (m, 6H) 1.18

3-(3-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Lightbrownoil, 55 mg,89% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.52 (m, 1H),7.37 (m, 5H), 7.27 (m, 2H), 4.48 (s, 2H), 3.65 (t, 4H), 3.39 (s, 2H),3.16 (s, 2H), 2.35 (t, 4H), 1.80 (m, 4H), 1.51 (m, 6H) 1.19

3-(3′-Diethylaminomethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spirot4.5]decan-2-oneColorless oil,11.1 mg, 30% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.56(m, 2H), 7.44 (m, 5H), 7.28 (m, 1H), 4.51 (s, 2H), 3.65 (s, 2H), 3.15(s, 2H), 2.58 (q, 4H), 1.80 (m, 4H), 1.51 (m, 6H), 1.08 (t, 6H) 1.20

3-(3′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneYellow oil,11.5 mg, 29% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.55 (m,2H), 7.42 (m, 5H), 7.26 (m, 1H), 4.51(s, 2H), 3.60 (s, 2H), 3.15 (s,2H), 2.50 (m, 4H), 2.29 (s, 3H), 2.23 (s, 6H), 1.81 (m, 4H), 1.51 (m,6H) 1.21

3-[3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-3-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneLight yellowoil, 31.9 mg,76% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.45(m, 8H), 4.51 (s, 2H), 3.59 (s, 2H), 3.15 (s, 2H), 2.49 (m, 8H), 2.30(s, 3H), 1.80 (m, 4H), 1.49 (m, 6H). 1.22

3-(4′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown solid,48.2 mg, 96% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.56 (m,4H), 7.43 (m, 2H), 7.35 (m, 2H), 4.48 (s, 2H), 3.63 (s, 2H), 3.15 (s,2H), 2.57 (q, 4H), 1.81 (m, 4H), 1.52 (m, 6H), 1.09 (t, 6H) 1.23

3-(4′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one White solid,34.8 mg, 66% NMR ¹H NMR (300 MHz, CDCl₃): δ(ppm) = 7.58 (m, 4H), 1.41 (m, 2H), 7.35 (m, 2H), 4.48 (s, 2H), 3.58 (s,2H), 3.14 (s, 2H), 2.50 (m, 4H), 2.82 (s, 3H), 2.23 (s, 6H), 1.56 (m,4H), 1.48 (m, 6H) 1.24

3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown solid,53.5 mg, 88% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.59 (m,4H), 7.40 (m, 2H), 7.34 (m, 2H), 4.47 (s, 2H), 3.56 (s, 2H), 3.14 (s,2H), 2.55 (m, 8H), 2.31 (s, 3H), 1.79 (m, 4H), 1.48 (m, 6H) 1.25

3-(4′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 16.7 mg,37% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.57(m, 4H), 7.42 (m, 2H), 7.35 (m, 2H), 4.48 (s, 2H), 3.75 (m, 4H), 3.57(s, 2H), 3.15 (s, 2H), 2.50 (m, 4H), 1.73 (m, 4H), 1.45 (m, 6H) 1.26

3-(3′-Morpholin-4-ylmethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-onePale yellowoil, 15.5 mg,26% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.43(m, 8H), 4.52 (s, 2H), 3.74 (m, 4H), 3.59 (s, 2H), 3.16 (s, 2H), 2.49(m, 4H), 1.69 (m, 4H), 1.39 (m, 6H) 1.27

3-(4′-Diethylaminomethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-onePale yellowoil, 44.7 mg,89% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.41(m, 8H), 4.51 (s, 2H), 3.64 (s, 2H), 3.15 (s, 2H), 2.58 (q, 4H), 1.80(m, 4H), 1.50 (m, 6H), 1.09 (t, 6H) 1.28

3-(4′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown oil,29.4 mg, 59% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.55 (m,3H), 7.44 (m, 4H), 7.25 (m, 1H), 4.50 (s, 2H), 3.58 (s, 2H), 3.15 (s,2H), 2.50 (m, 4H), 2.28 (s, 3H), 2.24 (s, 6H), 1.81 (m, 4H), 1.48 (m,6H) 1.29

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-3-carboxylicacid (2-dimethyl amino-ethyl)-amide White solid,53 mg, 90.4% NMR ¹H NMR(300 MHz, CDCl₃): δ (ppm) = 8.05 (t, 1H), 7.73 (m, 2H), 7.61 (d, 2H),7.44 (m, 1H), 7.34 (d, 2H), 6.98 (br, 1H), 4.47 (s, 2H), 3.56 (m, 2H),3.14 (s, 2H), 2.54 (t, 2H), 2.27 (s, 6H), 1.79 (m, 4H), 1.46 (m, 6H)1.30

3-{4-[6-(2-Morpholin-4-yl-ethylamino)-pyridin-3-yl]-benzyl}-1-oxa-3-aza-spiro[4.5]decan-2-onePale yellowoil, 41 mg,68% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.35(d, 1H), 7.68 (dd, 1H), 7.51 (d, 2H), 7.3 (t, 2H), 6.5 (d, 1H), 5.23(br, 1H), 4.45 (s, 2H), 3.74 (t, 4H), 3.41 (q, 2H), 3.13 (s, 2H), 2.65(t, 2H), 2.51 (t, 4H), 1.79 (m, 4H), 1.43 (m, 6H) 1.31

3-(4-Cyclohex-1-enyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Whitepowder,32 mg, 73% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.39 (dd, 2H),7.22 (d, 2H), 6.16 (m, 1H), 4.41 (s, 2H), 3.1 (s, 2H), 2.41 (br, 2H),2.23 (br, 2H), 1.8 (m, 7H), 1.66 (m, 7H) 1.32

3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-3-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown solid,35.7 mg, 70% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.52 (m,3H), 7.43 (m, 4H), 7.25 (m, 1H), 4.50 (s, 2H), 3.57 (s, 2H), 3.15 (s,2H), 2.52 (m, 8H), 2.31 (s, 3H), 1.80 (m, 4H), 1.49 (m, 6H) 1.33

3-(4′-Morpholin-4-ylmethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneColorless oil,26.3 mg, 56% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.53(m, 3H), 7.43 (m, 4H), 7.25 (m, 1H), 4.50 (s, 2H), 3.75 (m, 4H), 3.56(s, 2H), 3.15 (s, 2H), 2.50 (m, 4H), 1.81 (m, 4H), 1.49 (m, 6H) 1.34

3-(3′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown oil,35.6 mg, 70% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.60 (m,2H), 7.41 (m, 6H), 4.48 (s, 2H), 3.65 (s, 2H), 3.14 (s, 2H), 2.58 (q,4H), 1.80 (m, 4H), 1.55 (m, 6H), 1.08 (t, 6H) 1.35

3-(3′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-onePale yellowoil, 21.2 mg,58% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.59(m, 2H), 7.40 (m, 6H), 4.48 (s, 2H), 3.60 (s, 2H), 3.14 (s, 2H), 2.49(m, 4H), 2.29 (s, 3H), 2.23 (s, 6H), 1.78 (m, 4H), 1.55 (m, 6H) 1.36

3-[3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneDark brownsolid, 36.1 mg,74% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.45(m, 8H), 4.48 (s, 2H), 3.59 (s, 2H), 3.15 (s, 2H), 2.51 (m, 8H), 1.92(s, 3H), 1.82 (m, 4H), 1.50 (m, 6H) 1.37

3-(3′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneBrown solid,19.5 mg, 24% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.49 (m,8H), 4.49 (s, 2H), 3.74 (m, 4H), 3.59 (s, 2H), 3.15 (s, 2H), 2.51 (m,4H), 1.81 (m, 4H), 1.49 (m, 6H) 1.38

3-(2′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,37.2 mg, 65% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.57 (m,2H), 7.45 (m, 1H), 7.37 (m, 3H), 7.24 (m, 2H), 4.49 (s, 2H), 3.17 (s,2H), 1.81 (m, 4H), 1.45 (m, 6H) 1.39

3-(3′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,32.7 mg, 65% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.58 (m,2H), 7.36 (m, 5H), 7.06 (m, 1H), 4.49 (s, 2H), 3.15 (s, 2H), 1.80 (m,4H), 1.51 (m, 6H) 1.40

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-3-carbonitrileOff-whitesolid, 38.5 mg,75% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.84(m, 2H), 7.64 (m, 1H), 7.58 (m, 3H), 7.40 (m, 2H), 4.50 (s, 2H), 3.16(s, 2H), 1.80 (m, 4H), 1.49 (m, 6H) 1.41

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbonitrileColorless oil,35.3 mg, 69% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.73(m, 4H), 7.60 (m, 2H), 7.40 (m, 2H), 4.50 (s, 2H), 3.16 (m, 2H), 1.80(m, 4H), 1.51 (m, 6H) 1.42

3-(3′-Methoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 43.1 mg,83% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.60(m, 2H), 7.36 (m, 3H), 7.20 (m, 1H), 7.14 (m, 1H), 6.94 (m, 1H), 4.48(s, 2H), 3.89 (s, 3H), 3.15 (s, 2H), 1.79 (m, 4H), 1.50 (m, 6H) 1.43

3-(4′-Methoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,35.1 mg, 68% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.54 (m,4H), 7.33 (m, 2H), 7.00 (m, 2H), 4.47 (s, 2H), 3.87 (s, 3H), 3.14 (s,2H), 1.77 (m, 4H), 1.49 (m, 6H) 1.44

3-(2′,4′-Difluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,33 mg, 62% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.51 (m,2H), 7.42 (m, 1H), 7.36 (m, 2H), 6.94 (m, 2H), 4.49 (s, 2H), 3.16 (s,2H), 1.79 (m, 4H), 1.50 (m, 6H) 1.45

3-(3′,5′-Difluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Light yellowsolid, 44.5 mg,84% NMR ¹H NMR (300 MHz,CDCl₃): δ (ppm) = 7.55 (m, 2H), 7.37 (m, 2H), 7.11 (m, 2H), 6.81 (m,1H), 4.49 (s, 2H), 3.15 (s, 2H), 1.79 (m, 4H), 1.50 (m, 6H) 1.46

3-(3′,4′-Dimethoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,37.6 mg, 67% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.56 (m,2H), 7.33 (m, 2H), 7.14 (m, 2H), 6.97 (m, 1H), 4.47 (s, 2H), 3.97 (s,3H), 3.94 (s, 3H), 3.14 (s, 2H), 1.79 (m, 4H), 1.50 (m, 6H) 1.47

3-(2′-Methoxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Lightyellowoil, 45.1 mg,83% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.53 (m,1H), 7.35 (m, 7H), 4.51 (s, 2H), 4.34 (s, 2H), 3.35 (s, 3H), 3.19 (s,2H), 1.79 (m, 4H), 1.52 (m, 6H) 1.48

3-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one Off-whitesolid, 79 mg NMR ¹H NMR (300 MHz, CDCl₃): δ(ppm) = 7.37 (d, 2H), 7.23 (d, 2H), 6.16 (br, 1H), 4.41 (s, 2H), 3.53(br, 2H), 3.11 (m, 4H), 2.45 (br, 2H), 1.81 (m, 5H), 1.43 (m, 6H) 1.49

3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-oneWhite solid,53 mg, 46% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.57 (m,4H), 7.36 (d, 2H), 7.14 (t, 2H), 4.84 (s, 2H), 3.96 (m, 4H), 3.18 (s,2H), 2.01 (m, 4H), 1.83 (m, 2H), 1.67 (m, 2H) 1.50

3-(4′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,67 mg, 62% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.58 (d,4H), 7.43 (d, 2H), 7.34 (d, 2H), 5.99 (m, 1H), 5.37 (d, 1H), 5.25 (d,1H), 4.58 (s, 2H), 4.47 (s, 2H), 4.08 (dt, 2H), 3.14 (s, 2H), 1.78 (m,4H), 1.47 (m, 6H) 1.51

3-[4′-(3-Hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneWaxy whitesolid, 95% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.58 (dd,4H), 7.41 (d, 2H), 7.32 (d, 2H), 4.73 (s, 2H), 4.36 (m, 1H), 3.67 (s,2H), 3.13 (s, 2H), 2.88 (m, 1H), 2.7 (d, 2H), 2.61 (m, 1H), 2.39 (m,1H), 2.21 (m, 1H), 1.78 (m, 4H), m, 6H) 1.52

3-[4′-(Pyrrolidin-3-yloxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-onePale brownsolid, 59 mg,40% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.67(d, 4H), 7.43 (d, 2H), 7.3 (d, 2H), 4.76 (s, 2H), 4.69 (s, 2H), 4.16(br, 1H), 3.1 (s, 4H), 2.88 (br, 2H), 2.23 (br, 1H), 1.74 (m, 6H), 1.52(m, 6H) 1.53

3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneColorless oil,used in laterreactionwithout furtherpurification NMR ¹HNMR (300 MHz, CDCl₃): δ (ppm) = 7.6 (m, 3H), 7.53 (m, 1H), 7.45 (t, 1H),7.33 (d, 3H), 5.96 (m, 1H), 5.31 (m, 2H), 4.59 (s, 2H), 4.47 (s, 2H),4.09 (d, 2H), 3.09 (s, 2H), 1.78 (m, 4H), 1.48 (m, 6H) 1.54

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbaldehydeBeige solid,230 mg, 70% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 10 (s,1H), 7.92 (d, 2H), 7.71 (d, 2H), 7.58 (d, 2H), 7.37 (d, 2H), 4.45 (s,2H), 3.09 (s, 2H), 1.76 (m, 4H), 1.49 (m, 6H) 1.55

3-(3-Pyridin-4-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Colourlessoil,24 mg,50% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.71 (bs, 2H), 7.51(m, 6H), 4.52 (s, 2H), 3.16 (s, 2H), 1.79 (m, 4H), 1.48 (m, 6H) 1.56

3-[5-(4-Fluoro-phenyl)-pyridin-2-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneColourless oil,54 mg, 94% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.74(d, 1H), 7.85 (dd, 1H), 7.65 (m, 1H), 7.54 (m, 2H), 7.17 (t, 2H), 4.59(s, 2H), 3.32 (s, 2H), 1.82 (m, 4H), 1.47 (m, 6H) 1.57

3-(5-Cyclohex-1-enyl-pyridin-2-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneColourless oil,65 mg, 83% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.77(d, 1H), 7.61 (dd, 1H), 7.25 (t, 1H), 6.17 (m, 1H), 4.59 (s, 2H), 3.31(s, 2H), 2.38 (m, 2H), 2.22 (m, 2H), 1.58 (m, 14H)

Example 2.1:1-Oxa-3-aza-spiro[4.5]decan-2-one

1-Aminomethyl-cyclohexanol hydrogen chloride (250 mg, 1.5 mmol) andtriethylamine (0.21 mL, 1.5 mmol) were mixed in dichloromethane (5 mL),and the mixture was stirred for 15 min. Carbonic acid dipyridin-2-ylester (326 mg, 1.5 mmol) was then added, and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was dilutedwith ethyl acetate (10 mL), washed with water (2×4 mL), brine (2×4 mL);dried over anhydrous sodium sulfate and concentrated to give the titlecompound as a white powder (174 mg, 74%). ¹H NMR (300 MHz, CDCl₃): δ6.42 (br, 1H), 3.31 (s, 2H), 1.86 (m, 2H), 1.76 (m, 2H), 1.65 (m, 2H),1.47 (m, 4H).

Example 3.1 3-(4-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one

1-Oxa-spiro[4.5]decan-2-one (96 mg, 0.618 mmol), cesium carbonate(Cs₂CO₃) (605 mg, 1.855 mmol) and 1-bromomethyl-4-iodo-benzene (220 mg,0.742 mmol) were mixed in acetonitrile (2.5 mL). The reaction mixturewas heated at 70° C. for 5 hours, and the diluted with ethyl acetate (8mL). The mixture was washed with water (2×4 mL) and brine (2×4 mL). Thecombined organic phase was dried over anhydrous sodium sulfate andconcentrated. The crude residue was purified on silica gel eluting with5 to 25% ethyl acetate in hexane to give the product as a white powder(112 mg, 49%). ¹H NMR (300 MHz, CDCl₃): δ 7.68 (dd, 2H), 7.03 (dd, 2H),4.36 (s, 2H), 3.08 (s, 2H), 1.78 (m, 4H), 1.46 (m, 6H).

In a similar manner the following compounds were synthesized:

Example Structure Name Yield 3.2

3-Biphenyl-4-ylmethyl-1-oxa-3-aza-spiro[4.5]decan-2-one White powder,69mg, 95% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.62 (dd, 4 H), 7.44 (t,2 H), 7.34 (t, 3 H), 4.49 (s, 2 H), 3.15 (s, 2 H), 1.82 (m, 4 H), 1.54(m, 6 H) 3.3

3-(4-Phenoxy-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one White powder,69mg, 79% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.4 (t, 2 H), 7.33 (t, 2H), 7.13 (t, 1 H), 7.01 (m, 4 H), 4.41 (s, 2 H), 3.12 (s, 2 H), 1.79 (m,4 H), 1.46 (m, 6 H) 3.4

3-(3-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one White powder,1.0 g,84% NMR ¹H NMR (300 MHz, CDCl₃): □ (ppm) = 7.65 (m, 2 H), 7.27 (d, 1 H),7.11 (t, 1 H), 4.38 (s, 2 H), 3.11 (s, 2 H), 1.81 (m, 4 H), 1.47 (m, 6H) 3.5

3-Prop-2-ynyl-1-oxa-3-aza-spiro[4.5]decan-2-one Wine red oil,209 mg,100% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 4.02 (m, 2 H), 3.29 (s, 2H), 2.27 (m, 1 H), 1.6 (m, 10 H) 3.6

3-(5-Furan-2-yl-isoxazol-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneYellow solid,64 mg, 55% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.55 (m,1 H), 6.92 (dd, 1 H), 6.55 (m, 1 H), 6.47 (s, 1 H), 4.53 (s, 2 H), 3.27(s, 2 H), 1.79 (m, 4 H), 1.46 (m, 6 H) 3.7

3-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneYellow oil,31 mg, 24% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.88 (dd, 1H), 7.77 (dd, 1 H), 7.49 (m, 1 H), 7.26 (m, 1 H), 4.8 (s, 2 H), 3.49 (s,2 H), 1.95 (m, 2 H), 1.75 (m, 4 H), 1.42 (m, 4 H)

Example 4.1 3-(3-Pyridin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one

3-(3-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (0.148 mmol, 55 mg),2-tributylstannanyl-pyridine (0.222 mmol, 81.72 mg),tetrakispalladium(0) (0.03 mmol, 34.2 mg) were combined and dissolved intoluene (5 mL). The reaction mixture was left to stir at 110° C.overnight. It was then filtered through silica and the filtrate wasconcentrated in vacuo. The residue was purified by SPE flash columnchromatography using silica gel and ethyl/acetate/hexanes (0-50%) aseluent. The product was impure by NMR. Therefore, it was dissolved indichloromethane, and 2M hydrogen chloride in diethyl ether (10 mL) wasadded. This solution was concentrated in vacuo, the residue wasdissolved in water (10 mL) and washed with hexanes. The aqueous layerwas then neutralized using sodium bicarbonate and washed withdichloromethane. The organic layer was concentrated in vacuo to give thefinal product was a pale yellow gum (10 mg, 21%). ¹H NMR (300 MHz,CDCl₃): δ (ppm)=8.71 (m, 1H), 7.92 (m, 2H), 7.77 (m, 2H), 7.49 (m, 1H),7.37 (m, 1H), 7.27 (m, 1H), 4.53 (s, 2H), 3.14 (s, 2H), 1.78 (m, 4H),1.51 (m, 6H).

In a similar manner the following compounds were synthesized:

Example Structure Name Yield 4.2

3-(3-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Yellowoil,36 mg, 74% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.90 (m, 3 H),7.42 (m, 3 H), 4.50 (s, 2 H), 3.14 (s, 2 H), 1.79 (m, 4 H), 1.50 (m, 6H) 4.3

3-(4-Pyridin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 15 mg,31% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 8.7 (d,1 H), 7.98 (d, 2 H), 7.76 (m, 2 H), 7.4 (d, 2 H), 7.21 (m, 1 H), 4.5 (s,2 H), 3.12 (s, 2 H), 1.8 (m, 4 H), 1.39 (m, 6 H) 4.4

3-(4-Pyrazin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 5 mg,10% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 9.05 (d,1 H), 8.66 (d, 1 H), 8.54 (d, 1 H), 8.02 (d, 2 H), 7.7 (m, 2 H), 4.52(s, 2 H), 3.14 (s, 2 H), 1.8 (m, 4 H), 1.42 (m, 6 H) 4.5

3-(4-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one Paleyellowsolid, 21 mg,43% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.97 (d, 2H), 7.88 (d, 1 H), 7.38 (m, 3 H), 4.48 (s, 2 H), 3.12 (s, 2 H), 1.82 (m,4 H), 1.45 (m, 6 H)

Example 5.1 3-(4-Cyclohexyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one

3-(4-Cyclohex-1-enyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (Example1.31, 15 mg, 0.046 mmol) was dissolved in ethanol (3 mL) in a roundbottom flask. Pd/C (5 mg) was added and the flask was flushed withhydrogen and stirred at room temperature overnight. The reaction mixturewas filtered through a diatomaceous earth pad and the filtrate wasconcentrated in vacuo to give the title product as a white powder (15mg, quantitative yield). ¹H NMR (300 MHz, CDCl₃): δ (ppm)=7.19 (s, 4H),4.4 (s, 2H), 3.11 (s, 2H), 1.82 (m, 10H), 1.45 (m, 11H).

Example 6.1[3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-benzyl]-diethyl-amine

2-(3-Bromomethyl-phenyl)-5,5-dimethyl-[1,3,2]dioxaborinane (0.21 mmol,60 mg) and diethyl-amine (1 mL, >10 equiv) were combined and left tostir at 70° C. for 4 hours. The reaction mixture was then diluted withethyl acetate, concentrated in vacuo and dried on high vacuum for 1hour. The residue was then dissolved in dichloromethane, washed withwater, followed by brine, dried over anhydrous sodium sulfate andconcentrated in vacuo to give the final product as yellow oil (37.7 mg,65%). ¹H NMR (300 MHz, CDCl₃): 5 (ppm)=7.71 (m, 2H), 7.44 (m, 1H), 7.33(m, 1H), 3.79 (s, 4H), 3.59 (s, 2H), 2.54 (q, 4H), 1.06 (t, 6H), 1.04(s, 6H).

In a similar manner the following compounds were synthesized:

Example Structure Name Yield 6.2 

N-[3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-benzyl]-N,N′,N′-trimethyl-ethane-1,2-diamineYellow oil,38.2 mg,60% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.71 (m, 2H), 7.38 (m, 2 H), 3.79 (s, 4 H), 3.54 (s, 2 H), 2.49 (m, 4 H), 2.27 (s,3 H), 2.23 (s, 6 H), 1.04 (s, 6 H) 6.3 

1-[3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-benzyl]-4-methyl-piperazinean orange oil,40 mg, 63% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.70 (m,2 H), 7.42 (m, 1 H), 7.33 (m, 1 H), 3.78 (s, 4 H), 3.52 (s, 2 H), 2.44(m, 8 H), 2.34 (s, 3 H), 1.04 (s, 6 H). 6.4 

Diethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amineyellow solid,114.5 mg,99% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.78(m, 2 H), 7.39 (m, 2 H), 3.65 (s, 2 H), 2.57 (q, 4 H), 1.35 (s, 12 H),1.09 (t, 6 H). 6.5 

N,N,N′-Trimethyl-N′-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-ethane-1,2-diamineyellow oil116 mg,91% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.77 (m, 2H), 7.34 (m, 2 H), 3.33 (s, 2 H), 2.47 (m, 4 H), 2.23 (m, 9 H), 1.35 (s,12 H). 6.6 

1-Methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazineyellow solid,122 mg, 96% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.78 (m,2 H), 7.35 (m, 2 H), 3.53 (s, 2 H), 2.46 (m, 8 H), 2.32 (s, 3 H), 1.36(s, 12 H). 6.7 

4-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholineoff-white solid,96.2 mg, 79% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.78(m, 2 H), 7.36 (m, 2 H), 3.72 (t, 4 H), 3.53 (s, 2 H), 2.45 (t, 4 H),1.36 (s, 12 H) 6.8 

4-[3-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-benzyl]-morpholine yellowsolid,61.8 mg,102% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.72 (m, 2 H),7.43 (m, 1 H), 7.35 (m, 1 H), 3.79 (s, 4 H), 3.72 (t, 4 H), 3.52 (s, 2H), 2.46 (t, 4 H), 1.05 (s, 6 H) 6.9 

Diethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amineNMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.25 (m, 4 H), 3.77 (s, 2 H),2.66 (q, 4 H), 1.36 (s, 12 H), 1.06 (t, 6 H) 6.10

N,N,N′-Trimethyl-N′-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-ethane-1,2-diamineNMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.21 (m, 4 H), 3.82 (s, 2 H),2.79 (m, 2 H), 2.52 (m, 2 H), 2.47 (s, 3 H), 2.27 (s, 6 H), 1.34 (s, 12H) 6.11

1-Methyl-4-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazineNMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.29 (m, 4 H), 3.71 (s, 2 H),2.34 (m, 11 H), 1.36 (m, 12 H) 6.12

4-[2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine-1-carboxylicacid tert-butyl ester NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.31 (m, 4H), 3.7 (s, 2 H), 3.38 (br, 4 H), 2.37 (br, 4 H), 1.45 (s, 12 H), 1.35(s, 9 H)

Example 7.13-[4-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

3-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one(31 mg, 0.095 mmol), formaldehyde (1.5 mL) and formic acid (1.5 mL) weremixed and heated at 100° C. for 2 hours. The reaction mixture wasconcentrated; the residue was dissolved in DCM (2 mL) and neutralized byadding saturated NaHCO₃. The aqueous phase was extracted with DCM (2×3mL). The combined organic phase was dried over sodium sulfate andconcentrated in vacuo. The crude residue was purified on silica geleluting with 2M NH₃ in methanol/DCM (4:96) to give the product asoff-white solid (25 mg, 78%). ¹H NMR (300 MHz, CDCl₃): 6 (ppm) 7.39 (d,2H), 7.23 (d, 2H), 6.09 (br, 1H), 4.41 (s, 2H), 3.13 (br, 2H), 3.09 (s,2H), 2.7 (m, 2H), 2.59 (br, 2H), 2.42 (s, 3H), 1.78 (m, 4H), 1.54 (m,6H).

In a similar manner the following compound was synthesized:

Example Structure Name Yield 7.2

3-[4′-(1-Methyl-pyrrolidin-3-yloxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneWhite solid,23 mg, 74% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.59 (dd,4 H), 7.42 (d, 2 H), 7.33 (d, 2 H), 4.53 (s, 2 H), 4.47 (s, 2 H), 4.16(m, 1 H), 3.14 (s, 2 H), 2.7 (m, 3 H), 2.52 (m, 1 H), 2.38 (s, 3 H),2.16 (m, 1 H), 1.8 (m, 5 H), 1.52 (m, 6 H)

Example 8.13-(4′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decane-2,8-dione

3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-one(50 mg, 0.126 mmol) and 10% HCl (2 mL) were mixed in THF. The reactionmixture was heated at 60° C. for 3 hours. The reaction mixture wasquenched with saturated NaHCO₃ aqueous solution until PH=8. THF wasremoved under reduced pressure, and the aqueous phase was extracted withDCM (3×3 mL). The combined organic phases were dried over anhydroussodium sulfate and condensed in vacuo. The residue was purified onsilica gel eluting with 10-35% ethyl acetate in hexane to give theproduct as a white solid (35 mg, 78%). ¹H NMR (300 MHz, CDCl₃): δ (ppm)7.57 (m, 4H), 7.36 (d, 2H), 7.14 (t, 2H), 4.84 (s, 2H), 3.96 (m, 2H),3.18 (s, 2H), 2.01 (m, 4H), 1.83 (m, 2H).

Example 9.1[4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-ylmethoxy]-acetaldehyde

3-(4′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one(200 mg, 0.51 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and wascooled to −78° C. in dry ice-acetone bath. 03 was bubbled through thesolution for 15 min. Thin layer chromatography (TLC) confirmed thecompletion of the reaction at this stage. Thiourea was added to thereaction mixture and stirred at low temperature for 0.5 hr. The coolingbath was removed and the reaction mixture was allowed to warm to roomtemperature, and stirred overnight. The reaction mixture wasconcentrated, and the residue was purified on silica gel eluting with5-20% ethyl acetate in hexane to give the product as a white solid (80mg, 41%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 9.76 (s, 1H), 7.63 (m, 4H),7.44 (d, 2H), 7.35 (d, 2H), 4.7 (s, 2H), 4.47 (s, 2H), 4.16 (s, 2H),3.14 (s, 2H), 1.78 (m, 4H), 1.45 (m, 6H).

Example 10.13-[4′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-ylmethoxy]-acetaldehyde (110 mg, 0.279 mmol) was dissolved in ethanol (5mL). The solution was cooled in an ice-water bath, NaBH₄ (53 mg, 1.39mmol) was added at 0° C. in one shot, and the reaction mixture wasstirred at 0° C. for 1 hour. The reaction mixture was quenched withsaturate NaHCO₃ aqueous solution. The mixture was diluted with DCM (10mL). The aqueous phase was extracted with DCM (3×8 mL). The combinedorganic phase was dried over sodium sulfate and concentrated to give theproduct as a waxy solid (99 mg, 90%). ¹H NMR (300 MHz, CDCl₃): δ (ppm)7.65 (d, 4H), 7.42 (d, 2H), 7.32 (d, 2H), 4.73 (s, 2H), 4.61 (s, 2H),3.79 (t, 2H), 3.69 (t, 2H), 3.14 (s, 2H), 2.3 (br, 1H), 1.8 (m, 4H),1.47 (m, 6H).

Example 11.13-[4′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

3-[4′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one(85 mg, 0.215 mmol) was mixed with triethylamine (0.09 mL, 0.644 mmol)in DCM (3 mL). The mixture was cooled in ice-water bath. Methanesulfonylchloride (3.3 uL, 0.49 mmol) was added and the reaction mixturewas allowed to warm to room temperature. The stirring was continued forfurther 2 hours. The reaction mixture was quenched with saturate NaHCO₃aqueous solution (3 mL). The aqueous phase was extracted with DCM (3×3mL). The combined organic phase was dried over sodium sulfate andconcentrated to give a brown oil which was mixed with dimethyl amine (4mL, 6.44 mmol) in a screw cap vial and heated at 60-70° C. for 3.5hours. The reaction mixture was concentrated, redissolved in DCM (5 mL)and stirred with saturated NaHCO₃ aqueous solution (3 mL). The aqueousphase was extracted with DCM (3×4 mL). The combined organic phases weredried over sodium sulfate and concentrated to give a pale brown oil,which was purified on silica gel eluting with DCM containing 1-2.5% 2Mammonia in methanol to give the product as a white solid (74 mg, 82%).¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.56 (dd, 4H), 7.41 (d, 2H), 7.29 (d,2H), 4.64 (s, 2H), 4.45 (s, 2H), 3.56 (t, 2H), 3.12 (s, 2H), 2.54 (t,2H), 2.27 (s, 6H), 1.75 (m, 4H), 1.52 (m, 6H).

In a similar manner the following compounds were synthesized:

Example Structure Name Yield 11.2

3-[3′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneOff-whitesolid, 53 mg,83.7% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.65(d, 3 H), 7.57 (d, 1 H), 7.41 (t, 1 H), 7.31 (d, 3 H), 4.6 (s, 2 H),4.46 (s, 2 H), 3.59 (t, 2 H), 3.13 (s, 2 H), 2.55 (t, 2 H), 2.27 (s, 6H), 1.78 (m, 4 H), 1.48 (m, 6 H) 11.3

3-[3′-(2-Methylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-oneColorless oil,56 mg, 91.4% NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.59(d, 3 H), 7.56 (d, 1 H), 7.42 (t, 1 H), 7.32 (d, 3 H), 4.69 (s, 2 H),4.58 (s, 2 H), 3.63 (t, 2 H), 3.13 (s, 2 H), 2.79 (br, 2 H), 2.44 (s, 3H), 1.76 (m, 4 H), 1.48 (m, 7 H)

Example 12.13-[3′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one(260 mg, 0.664 mmol) was dissolved in DCM/methanol (4:1, 7.5 mL) and wascooled to −78° C. in dry ice-acetone bath. O₃ was bubbled through thesolution for 15 min. Thin layer chromatography (TLC) confirmed thecompletion of the reaction at this stage. The DCM was evaporated invacuo; ethanol (5 mL) was added and the solution was cooled in ice-waterbath to 0° C. NaBH₄ (175 mg, 7 eq.) was added and the reaction wasstirred at the temperature of 0-5° C. for one hour then at roomtemperature for 1.5 hour. The reaction mixture was quenched withsaturated NaHCO₃ aqueous solution. The aqueous phase was extracted withDCM (3×8 mL), the combined organic phases were washed with brine (5 mL),dried over sodium sulfate and concentrated. The crude residue waspurified on silica gel eluting with 20-50% ethyl acetate in hexane togive the product (134 mg, 51%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.59(d, 3H), 7.52 (d, 1H), 7.41 (t, 1H), 7.32 (d, 3H), 4.85 (s, 2H), 4.45(s, 2H), 3.77 (br, 2H), 3.62 (t, 2H), 3.12 (s, 2H), 2.48 (br, 1H), 1.72(m, 4H), 1.5 (m, 6H).

In a similar manner the following compound was synthesized:

Example Structure Name Yield 12.2

3-(3′-Hydroxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one29 mg NMR ¹H NMR (300 MHz, CDCl₃): δ (ppm) = 7.6 (d, 3 H), 7.52 (d, 1H), 7.44 (t, 1 H), 7.35 (t, 3 H), 4.78 (br, 2 H), 4.47 (s, 2 H), 3.1 (s,2 H), 2.05 (br, 1 H), 1.78 (m, 4 H), 1.52 (m, 6 H)

Example 13.13-[4′-(3-Hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbaldehyde(50 mg, 0.143 mmol) was mixed with (R)-(−)-3-pyrrolidinol hydrochloride(20 mg, 0.157 mmol) in DCE (2.5 mL). Na(OAc)₃BH was added as a solid atroom temperature and the reaction was stirred overnight. The reactionwas quenched with saturated aqueous NaHCO₃ solution. The aqueous phasewas extracted with DCM (3×5 mL), the combined organic phases were washedwith brine (5 mL), dried over sodium sulfate and concentrated. The cruderesidue was purified on silica gel eluting with DCM containing 0.5-2% 2Mammonia in methanol to give the product as off-white solid (34 mg,56.5%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.59 (dd, 4H), 7.38 (d, 2H),7.29 (d, 2H), 4.42 (s, 2H), 4.37 (m, 1H), 3.69 (s, 2H), 3.13 (s, 2H),2.87 (m, 1H), 2.67 (d, 1H), 2.58 (dd, 1H), 2.37 (m, 2H), 2.2 (m, 1H),1.76 (m, 4H), 1.51 (m, 6H).

Example 14.1 (5-Bromo-pyridin-2-yl)-methanol

A mixture of 5-bromo-pyridine-2-carbaldehyde (0.5 g, 2.68 mmol) inethanol (30 mL) was cooled in an ice bath. Sodium borohydride (0.41 g,10.75 mmol) was added and the reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was concentrated, dried,the residue dissolved in dichloromethane (30 mL) and quenched with asaturated aqueous sodium bicarbonate solution. The organic phase wasseparated and the aqueous phase was extracted further withdichloromethane (2×10 mL). The combined organic phase was dried oversodium sulfate and concentrated to give the product as an off-whitesolid (426 mg, 84%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 8.61 (d, 1H), 7.82(dd, 1H), 7.23 (d, 1H), 4.73 (s, 2H), 3.92 (bs, 1H).

Example 15.1 Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester

A mixture of (5-Bromo-pyridin-2-yl)-methanol (60 mg, 0.32 mmol) indichloromethane (2 ml) was cooled in as ice bath. To the mixture wasthen added triethylamine (0.13 mL, 0.96 mmol) followed bymethanesulfonyl chloride (0.05 mL, 0.64 mmol). The reaction mixture wasstirred at room temperature for 2 hours. To the reaction mixture wasadded saturated aqueous sodium bicarbonate (5 mL). The organic phase wasseparated and the aqueous phase extracted further with dichloromethane(2×5 mL). The combined organic phase was washed with brine, dried oversodium sulfate and concentrated to give the product as a pale brown oil.

Example 16.13-(5-Bromo-pyridin-2-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one

Methanesulfonic acid 5-bromo-pyridin-2-ylmethyl ester (85 mg, 0.319mmol), cesium carbonate (312 mg, 0.957 mmol) and1-oxa-3-aza-spiro[4.5]decan-2-one (49.5 mg, 0.319 mmol) were mixed inacetonitrile (2 mL). The reaction mixture was heated at 70° C. for 5hours and then diluted with dichloromethane (8 mL). The mixture waswashed with water (3 mL) and brine (3 mL). The combined organic phasewas dried over sodium sulfate and concentrated. The residue was purifiedon silica gel eluting with 10 to 20% ethyl acetate in hexanes to givethe product as an off-white solid (60 mg, 58%). ¹H NMR (300 MHz, CDCl₃):δ 8.6 (d, 1H), 7.81 (dd, 1H), 7.23 (d, 1H), 4.49 (s, 2H), 3.27 (s, 2H),1.79 (m, 4H), 1.47 (m, 6H).

Example 17.1 4-(4-Iodo-benzyl)-morpholine

1-Bromomethyl-4-iodo-benzene (320 mg, 1.08 mmol) and morpholine (1 mL,11.47 mmol) were combined. The reaction mixture was heated at 70° C. for4 hours and then diluted with ethyl acetate. The resulting mixture wasfiltered and the filtrate was concentrated and dried. The residue wasthen dissolved in dichloromethane (10 mL), washed with water (4 mL),washed with brine (4 mL), dried over sodium sulfate and concentrated togive the product as an off-white solid (300 mg, 92%). ¹H NMR (300 MHz,CDCl₃): δ 7.64 (d, 2H), 7.09 (d, 2H), 3.7 (t, 4H), 3.43 (s, 2H), 2.43(t, 4H).

Example 18.13-[3(4-morpholin-4-ylmethyl-phenyl)-prop-2-ynyl]-1-oxa-3-aza-spiro[4.5]decan-2-one

3-Prop-2-ynyl-1-oxa-3-aza-spiro[4.5]decan-2-one (55 mg, 0.284 mmol),4-(4-iodo-benzyl)-morpholine (95 mg, 0.313 mmol),tetrakis(triphenylphosphine)palladium (17 mg, 0.0142 mmol), copperiodide (6 mg, 0.0284 mmol) and triethylamine (0.12 mL, 0.853 mmol) weremixed in acetonitrile (1 mL) under argon. The reaction mixture wasstirred at room temperature for 1 hour and then diluted withdichloromethane (6 mL). The mixture was washed with water (4 mL), washedwith brine (4 mL), dried over sodium sulfate and concentrated. Theresidue was purified on silica gel eluting with 10 to 25% ethyl acetatein hexanes. The isolated product was treated with 2M hydrochloric acidin diethyl ether to make the hydrochloric acid salt. The salt was thendissolved in water, washed with hexanes and the aqueous phase then madealkaline using aqueous saturated sodium bicarbonate. The aqueous mixturewas then extracted with dichloromethane and the organic phase dried oversodium sulfate and concentrated to give the product as an off-whitesolid (43 mg, 41%). ¹H NMR (300 MHz, CDCl₃): δ 7.38 (d, 2H), 7.29 (d,2H), 4.31 (s, 2H), 3.71 (t, 4H), 3.49 (s, 2H), 3.4 (s, 2H), 2.43 (t,4H), 1.83 (m, 4H), 1.54 (m, 6H).

Example 19.1 3-Fluoro-N-hydroxy-benzamidine

3-Fluorobenzonitrile (2.5 g, 0.021 mol), diisopropylethyl amine (10.8mL, 0.062 mol) and hydroxylamine hydrochloride (4.3 g, 0.062 mol) weremixed in ethanol (30 mL). The reaction mixture was stirred at 70° C.overnight. The reaction mixture was cooled to room temperature andconcentrated to half the original volume. The residue was added to amixture of dichloromethane (200 mL) and water (60 mL). The mixture wasbasified to pH 9 using 2N NaOH and the organic phase was separated. Theaqueous phase was extracted further with dichloromethane (2×50 mL) andthe combined organic phase was washed with water (75 mL), washed withbrine (75 mL), dried over sodium sulfate and concentrated to give theproduct as a yellow solid (2.8 g, 89%). ¹H NMR (300 MHz, CDCl₃): δ 8.05(bs, 1H), 7.39 (m, 3H), 7.16 (m, 1H), 4.88 (bs, 2H).

Example 20.1 5-Chloromethyl-3-(3-fluoro-phenyl)-[1,2,4]oxadiazole

3-Fluoro-N-hydroxy-benzamidine (1.4 g, 9.08 mmol), chloroacetic acid(0.94 g, 9.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (1.91 g, 9.99 mmol) and 1-hydroxybenzotriazole hydrate(1.35 g, 9.99 mmol) were mixed in N,N-dimethylformamide (15 mL). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was diluted with ethyl acetate (50 mL), washed with water (50mL), washed with aqueous saturated sodium bicarbonate (75 mL), washedwith water again (50 mL) and washed with brine (50 mL). The organicphase was dried over sodium sulfate and concentrated to give a solid.The solid was dissolved in N,N-dimethylformamide (10 mL) and thereaction mixture stirred at 120° C. for 1.5 hours. The reaction mixturewas cooled to room temperature, diluted with ethyl acetate (100 mL),washed with water (3×50 mL) and washed with brine (50 mL). The organicphase was dried over sodium sulfate and concentrated. The residue waspurified on silica gel eluting with 10 to 30% ethyl acetate in hexanesto give the product as a yellow oil (1.15 g, 60%). ¹H NMR (300 MHz,CDCl₃): δ 7.91 (dd, 1H), 7.82 (m, 1H), 7.5 (m, 1H), 7.25 (m, 1H), 4.78(s, 2H).

1. A compound according to Formula I:

wherein: R¹ is selected from the group consisting of H, hydroxy, F, Cl,Br, I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, methylenedioxy and ethylenedioxy; L isselected from the group consisting of alkylene, alkenylene andalkynylene wherein any hydrogen atom of L may be independentlysubstituted with one or more substituents selected from the groupconsisting of hydroxy, F, Cl, Br, I, alkyl, alkylhalo and O-alkyl; A isselected from the group consisting of aryl and heteroaryl; B is selectedfrom the group consisting of alkylene, aryl, heteroaryl, cycloalkyl andheterocycloalkyl; D is selected from the group consisting of alkylene,O,O-alkylene and alkylene-O; E is selected from the group consisting ofaryl, heteroaryl, cycloalkyl and heterocycloalkyl; m and n areindependently selected from the group consisting of 0, 1, 2, 3 and 4; xand y are independently selected from the group consisting of 0 and 1;wherein any of A, B and E may be substituted with up to 4 substituentsindependently selected from the group consisting of hydroxy, F, Cl, Br,I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, alkyleneOR², O-alkyleneOR², (CO)R²,O(CO)R², alkyleneO(CO)R², alkylene(CO)R², O-alkylene(CO)R², CO₂R,alkyleneCO₂R², O-alkyleneCO₂R², alkylenecyano, O-alkylenecyano,O(CN)OR², NR²R³, alkyleneNR²R³, O-alkyleneNR²R³, (CO)NR²R³,alkylene(CO)NR²R³, O—(CO)NR²R³, O-alkylene(CO)NR²R³, NR²(CO)R³,alkyleneNR²(CO)R³, O-alkyleneNR²(CO)R³, NR²(CO)NR³R⁴,alkyleneNR²(CO)NR³R⁴, and wherein R² and R⁴ are independently selectedfrom the group consisting of H and alkyl; R³ is selected from the groupconsisting of H, alkyl and alkylene-NR²R⁴; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein mis 1, of Formula Ia:

wherein R¹, n, L, A, B, D, E, x and y are as defined in claim
 1. 3. Acompound according to claim 1, wherein m is 1, and x and y are each 0,of Formula Ib:

wherein R¹, n, L, A and B are as defined for Formula I.
 4. A compoundaccording to claim 1, wherein m is 1, x and y are each 0, A and B areboth aryl wherein aryl is phenyl, of Formula Ic:

wherein R¹, n and L are as defined for Formula I, wherein each phenylmay be substituted with up to 4 substituents independently selected fromthe group consisting of hydroxy, F, Cl, Br, I, nitro, CN, alkyl,alkylhalo, O-alkyl, O-alkylhalo, alkenyl, O-alkenyl, alkynyl, O-alkynyl,alkyleneOR², O-alkyleneOR², (CO)R², O(CO)R², alkyleneO(CO)R²,alkylene(CO)R², O-alkylene(CO)R², CO₂R, alkyleneCO₂R², O-alkyleneCO₂R²,alkylenecyano, O-alkylenecyano, O(CN)OR², NR²R³, alkyleneNR²R³,O-alkyleneNR²R³, (CO)NR²R³, alkylene(CO)NR²R³, O—(CO)NR²R³,O-alkylene(CO)NR²R³, NR²(CO)R³, alkyleneNR²(CO)R³, O-alkyleneNR²(CO)R³,NR²(CO)NR³R⁴, alkyleneNR²(CO)NR³R⁴, and wherein R² and R⁴ areindependently selected from the group consisting of H and alkyl, and R³is selected from the group consisting of H, alkyl and alkylene-NR²R⁴. 5.A compound according to claim 1, wherein L is an alkylene group.
 6. Acompound according to claim 1, wherein A is an aryl group.
 7. A compoundaccording to claim 1, wherein A is a heteroaryl group.
 8. A compoundaccording to claim 1, wherein B is an aryl group.
 9. A compoundaccording to claim 1, wherein D is an alkylene group.
 10. A compoundaccording to claim 1, wherein E is a heterocycloalkyl group.
 11. Apharmaceutical composition comprising a compound according to claim 1and a pharmaceutically acceptable carrier or excipient.
 12. A compoundselected from the group consisting of:3-(2′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(2′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(2′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[2′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(2′-piperazin-1-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Phenoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Pyridin-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(4-Methyl-piperazin-1-yl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Fluoro-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Phenoxy-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3-Pyridin-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Pyridin-4-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Pyrimidin-5-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Thiophen-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Thiophen-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3-Thiophen-3-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Diethylaminomethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-3-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Morpholin-4-ylmethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Diethylaminomethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-3-carboxylicacid (2-dimethyl amino-ethyl)-amide;3-{4-[6-(2-Morpholin-4-yl-ethylamino)-pyridin-3-yl]-benzyl}-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Cyclohex-1-enyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-3-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Morpholin-4-ylmethyl-biphenyl-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Diethylaminomethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[3′-(4-Methyl-piperazin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(2′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-3-carbonitrile;4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbonitrile;3-(3′-Methoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Methoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(2′,4′-Difluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′,5′-Difluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′,4′-Dimethoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(2′-Methoxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-one;3-(4′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(3-Hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(Pyrrolidin-3-yloxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Allyloxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-carbaldehyde;3-(3-Pyridin-4-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[5-(4-Fluoro-phenyl)-pyridin-2-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(5-Cyclohex-1-enyl-pyridin-2-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-Biphenyl-4-ylmethyl-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Phenoxy-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(5-Furan-2-yl-isoxazol-3-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3-Pyridin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Pyridin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Pyrazin-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Thiazol-2-yl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4-Cyclohexyl-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4-(1-Methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(1-Methyl-pyrrolidin-3-yloxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Fluoro-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decane-2,8-dione;[4′-(2-Oxo-1-oxa-3-aza-spiro[4.5]dec-3-ylmethyl)-biphenyl-4-ylmethoxy]-acetaldehyde;3-[4′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[3′-(2-Dimethylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[3′-(2-Methylamino-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[3′-(2-Hydroxy-ethoxymethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(3′-Hydroxymethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-[4′-(3-Hydroxy-pyrrolidin-1-ylmethyl)-biphenyl-4-ylmethyl]-1-oxa-3-aza-spiro[4.5]decan-2-one;and3-[3(4-morpholin-4-ylmethyl-phenyl)-prop-2-ynyl]-1-oxa-3-aza-spiro[4.5]decan-2-one.13. A compound according to claim 12 selected from the group consistingof:3-(2′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Phenoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-one,and 3-Biphenyl-4-ylmethyl-1-oxa-3-aza-spiro[4.5]decan-2-one.
 14. Amethod for the treatment or prevention of neurological and psychiatricdisorders associated with glutamate dysfunction in an animal in need ofsuch treatment, comprising the step of administering to said animal atherapeutically effective amount of a compound according to Formula I:

wherein: R¹ is selected from the group consisting of H, hydroxy, F, Cl,Br, I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, methylenedioxy and ethylenedioxy; L isselected from the group consisting of alkylene, alkenylene andalkynylene wherein any hydrogen atom of L may be independentlysubstituted with one or more substituents selected from the groupconsisting of hydroxy, F, Cl, Br, I, alkyl, alkylhalo and O-alkyl; A isselected from the group consisting of aryl and heteroaryl; B is selectedfrom the group consisting of alkylene, aryl, heteroaryl, cycloalkyl andheterocycloalkyl; D is selected from the group consisting of alkylene,O,O-alkylene and alkylene-O; E is selected from the group consisting ofaryl, heteroaryl, cycloalkyl and heterocycloalkyl; m and n areindependently selected from the group consisting of 0, 1, 2, 3 and 4; xand y are independently selected from the group consisting of 0 and 1;wherein any of A, B and E may be substituted with up to 4 substituentsindependently selected from the group consisting of hydroxy, F, Cl, Br,I, nitro, CN, alkyl, alkylhalo, O-alkyl, O-alkylhalo, alkenyl,O-alkenyl, alkynyl, O-alkynyl, alkyleneOR², O-alkyleneOR², (CO)R²,O(CO)R², alkyleneO(CO)R², alkylene(CO)R², O-alkylene(CO)R², CO₂R,alkyleneCO₂R², O-alkyleneCO₂R², alkylenecyano, O-alkylenecyano,O(CN)OR², NR²R³, alkyleneNR²R³, O-alkyleneNR²R³, (CO)NR²R³,alkylene(CO)NR²R³, O—(CO)NR²R³, O-alkylene(CO)NR²R³, NR²(CO)R³,alkyleneNR²(CO)R³, O-alkyleneNR²(CO)R³, NR²(CO)NR³R⁴,alkyleneNR²(CO)NR³R⁴, and wherein R² and R⁴ are independently selectedfrom the group consisting of H and alkyl; R³ is selected from the groupconsisting of H, alkyl and alkylene-NR²R⁴; or a pharmaceuticallyacceptable salt thereof.
 15. The method according to claim 14, whereinthe neurological or psychiatric disorder is selected from cerebraldeficit subsequent to cardiac bypass surgery and grafting, stroke,cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia,cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induceddementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateralsclerosis, ocular damage, retinopathy, cognitive disorders, idiopathicand drug-induced Parkinson's disease, muscular spasms and disordersassociated with muscular spasticity including tremors, epilepsy,convulsions, cerebral deficits secondary to prolonged statusepilepticus, migraine, migraine headache, urinary incontinence,substance tolerance, substance withdrawal, psychosis, schizophrenia,anxiety, generalized anxiety disorder, panic disorder, social phobia,obsessive compulsive disorder, and post-traumatic stress disorder(PTSD), mood disorders, depression, mania, bipolar disorders, circadianrhythm disorders, jet lag, shift work, trigeminal neuralgia, hearingloss, tinnitus, macular degeneration of the eye, emesis, brain edema,pain, acute pain, chronic pain, severe pain, intractable pain,neuropathic pain, inflammatory pain, and post-traumatic pain, tardivedyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivitydisorder, or conduct disorder.
 16. The method according to claim 15,wherein the neurological or psychiatric disorder is selected fromAlzheimer's disease, cerebral deficits secondary to prolonged statusepilepticus, substance tolerance, substance withdrawal, psychosis,schizophrenia, anxiety, generalized anxiety disorder, panic disorder,social phobia, obsessive compulsive disorder, and post-traumatic stressdisorder (PTSD), mood disorders, depression, mania, or bipolardisorders.
 17. The method according to claim 16, wherein theneurological or psychiatric disorder is selected from Alzheimer'sdisease, schizophrenia, depression or bipolar disorders.
 18. A methodfor the treatment or prevention of neurological and psychiatricdisorders associated with glutamate dysfunction in an animal in need ofsuch treatment, comprising the step of administering to said animal atherapeutically effective amount of a compound selected from:3-(2′-Morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Phenoxy-biphenyl-4-ylmethyl)-1-oxa-3-aza-spiro[4.5]decan-2-one;3-(4′-Fluoro-biphenyl-4-ylmethyl)-1,9,12-trioxa-3-aza-dispiro[4.2.4.2]tetradecan-2-one,and 3-Biphenyl-4-ylmethyl-1-oxa-3-aza-spiro[4.5]decan-2-one; or apharmaceutically acceptable salt thereof.
 19. The method according toclaim 18, wherein the neurological or psychiatric disorder is selectedfrom cerebral deficit subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia,AIDS-induced dementia, Alzheimer's disease, Huntington's Chorea,amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitivedisorders, idiopathic and drug-induced Parkinson's disease, muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, cerebral deficits secondary to prolongedstatus epilepticus, migraine, migraine headache, urinary incontinence,substance tolerance, substance withdrawal, psychosis, schizophrenia,anxiety, generalized anxiety disorder, panic disorder, social phobia,obsessive compulsive disorder, and post-traumatic stress disorder(PTSD), mood disorders, depression, mania, bipolar disorders, circadianrhythm disorders, jet lag, shift work, trigeminal neuralgia, hearingloss, tinnitus, macular degeneration of the eye, emesis, brain edema,pain, acute pain, chronic pain, severe pain, intractable pain,neuropathic pain, inflammatory pain, and post-traumatic pain, tardivedyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivitydisorder, or conduct disorder.
 20. The method according to claim 19,wherein the neurological or psychiatric disorder is selected fromAlzheimer's disease, cerebral deficits secondary to prolonged statusepilepticus, substance tolerance, substance withdrawal, psychosis,schizophrenia, anxiety, generalized anxiety disorder, panic disorder,social phobia, obsessive compulsive disorder, and post-traumatic stressdisorder (PTSD), mood disorders, depression, mania, or bipolardisorders.
 21. The method according to claim 20, wherein theneurological or psychiatric disorder is selected from Alzheimer'sdisease, schizophrenia, depression or bipolar disorders.